Given the accelerating appearance of antimicrobial resistance, there is an urgent need for more fundamental research into novel antibiotic strategies. The work in this thesis helps to address this... Show moreGiven the accelerating appearance of antimicrobial resistance, there is an urgent need for more fundamental research into novel antibiotic strategies. The work in this thesis helps to address this global problem by developing new antibiotic compounds, inspired by the antibacterial mechanisms of the natural antibiotic bacitracin. By unravelling the unique mechanism of action that bacitracin employs, we discovered that the inclusion of a small hydrophobic group in key locations of the molecule results in a dramatic enhancement of antibacterial activity, in some cases more than 100 times more potent than bacitracin. Crucially we found that the most potent analogues are particularly active against antibiotic-resistant bacteria including those bearing clinically challenging resistance genes. In doing so we have developed potent next-generation variants of this classic antibiotic and have taken important steps in the fight against antimicrobial resistance. Show less
After standard surgery for neck hernias, about 25% of patients report low satisfaction. This thesis applied inferential statistics to clinical data and Machine Learning to medical imaging, with the... Show moreAfter standard surgery for neck hernias, about 25% of patients report low satisfaction. This thesis applied inferential statistics to clinical data and Machine Learning to medical imaging, with the goal of finding out where differences in functional outcomes after surgery come from and how artificial intelligence can improve the diagnostic and prognostic process. The initial idea that differences in functional recovery were due to surgical technique was refuted by an RCT from this dissertation. The differences in functional recovery between three different surgical groups (removal of the intervertebral disc without artificial material, placement of intervertebral disc prosthesis, and fusion of vertebrae with a cage) were found to be minimal. It was striking that not surgical technique, but patients' mental health and preoperative, radiological imaging were found to be predictive of clinical recovery after surgery. Although the intervertebral disc prosthesis did not deliver on the promise of preserving mobility and thus could not prevent degeneration at adjacent levels, using Deep Learning based solely on the preoperative MRI of the neck, researchers were able to predict, among other things, which patients would require reoperation after surgery for that adjacent degeneration. The Deep Learning model did that significantly better than an experienced neuroradiologist and neurosurgeon. Such Deep Learning models eliminate the need for time-consuming questionnaires and are thus more cost-effective and less stressful for the patient, while they can be used to identify radiological features important for predicting the postoperative course. After validation with larger radiological datasets, these models can support clinical decision-making and help physicians develop personalized treatment strategies. Challenges within image analysis research for the spine lies in integrating different models into one automated process, preferably built into the electronic health record. Show less
An Active Galactic Nucleus (AGN) is a highly luminous region at the center of a galaxy, powered by the accretion into a supermassive black hole and emitting energy from radio waves to gamma rays,... Show moreAn Active Galactic Nucleus (AGN) is a highly luminous region at the center of a galaxy, powered by the accretion into a supermassive black hole and emitting energy from radio waves to gamma rays, often outshining the host galaxy. In the context of the AGN unification paradigm, the concept of the dusty “torus” plays a crucial role to discern between Type-1 and Type-2 AGNs depending on whether it obscures the AGN from the observer’s line of sight. NGC 1068, a well-studied AGN across the electromagnetic spectrum, is a nearby barred galaxy (d=14.4 Mpc) considered the prototypical Type-2. Using MATISSE at the VLTI, we have obtained direct evidence of the dusty torus enshrouding the AGN in NGC 1068. The multi-band capabilities of the instrument in the infrared wavelengths and the high spatial resolution that the interferometric technique can achieve have enabled us to study in detail the characteristics of the obscuring dust and its spatial distribution. We further analyse ALMA observations of the molecular gas with a comparable angular resolution. The revealed kinematics suggest an ongoing merger event, potentially contributing to the observed asymmetries in the torus and the water-maser disk, offering new insights into the dynamic processes in AGNs. Show less
People belonging to sexual minorities and people who do not conform to gender stereotypical roles still have a disadvantaged position in society. To promote inclusivity, it is important to... Show morePeople belonging to sexual minorities and people who do not conform to gender stereotypical roles still have a disadvantaged position in society. To promote inclusivity, it is important to understand how individuals are socialized into heteronormativity: everyday ways in which heterosexuality and traditional gender roles are positioned as normal and natural. In this dissertation, I examine the extent to which individuals (adolescents in particular) are socialized with heteronormativity by the national context in which they live, by Dutch schoolbooks and within Dutch families.Individuals appear to be socialized with heteronormativity in different ways: at the national level, progressive laws appear to be important, in school textbooks gender stereotypical patterns, underrepresentation of women and exclusion of sexual minorities, and within families the transmission of gender stereotypical and homophobic attitudes from parents to children. It appears that there is still a long way to go to achieve inclusion based on gender and sexual orientation. It seems important to continue to investigate both conscious and unconscious heteronormative messages and to address them in policy. More representation of counter-stereotypical role models and the normalization of public expressions and relationships of lesbian women and gay men seem necessary. Show less
Prematurely born neonates require, amongst others, pharmaceutical therapy. Dosing guidelines for these therapies are often based on data from term born neonates or older infants, while these are... Show morePrematurely born neonates require, amongst others, pharmaceutical therapy. Dosing guidelines for these therapies are often based on data from term born neonates or older infants, while these are not necessarily similar to prematurely born neonates. When suboptimal dosing guidelines are applied the neonates are at risk for under- or overdosing. In this thesis the pharmacokinetics and pharmacodynamics of a variety of drugs frequently used in preterm neonates were characterized, ultimately to optimize treatment. Specifically, caffeine, ibuprofen and fluconazole were studied which are drugs to treat apnea of prematurity, to close a patent ductus arteriosus and to treat or prevent infections with Candida in newborns, respectively. These drugs were introduced and used in clinical practice without sufficient knowledge, especially on appropriate dosing for this subpopulation. For caffeine and ibuprofen we found that the clearance rapidly increases with postnatal age, while for fluconazole clearance is better reflected by body weight and serum creatinine. For these drugs dosing guidelines were proposed based on identified covariates for their pharmacokinetics. Ibuprofen therapy was further investigated by examining the course of spontaneous closure of the ductus arteriosus, and evaluating the effects of ibuprofen exposure and patient characteristics simultaneously. Show less
From the second half of the third century BCE onwards, Rome was inundated with ‘non-local’ objects. The great Roman conquests of the period, like the sack of Syracuse in 211 BCE, brought objects... Show moreFrom the second half of the third century BCE onwards, Rome was inundated with ‘non-local’ objects. The great Roman conquests of the period, like the sack of Syracuse in 211 BCE, brought objects from all the conquered regions to the city of Rome. Among these objects was a vast number of ‘non-local’ statues that moved from the Greek world to Rome. In the city, they were put on display in public locations and became an integrated part of the Roman cultural environment and daily life. Such statues changed Rome on multiple levels – and this was also perceived as such by the Romans themselves.This dissertation investigates the introduction and impact of Greek statues in Republican Rome through an archaeological perspective. It attempts to study the appropriation of such ‘non-local’ statues, and the shock of the new that society experienced, from an object perspective, by analysing the biographies of some specifically selected individual statues. As such, this research explores how Greek statues became integrated into the city of Rome and how their appropriation was connected to change and innovation in Roman society. Show less
In this dissertation various aspects of the Roman economy and of Roman society related to food are reconstructed based on an interdisciplinary approach. The study focuses on the city of Rome in the... Show moreIn this dissertation various aspects of the Roman economy and of Roman society related to food are reconstructed based on an interdisciplinary approach. The study focuses on the city of Rome in the period between the 2nd century BCE and the beginning of the 4th century CE. First of all, the food culture and eating habits of the Romans are reconstructed. Subsequently, the food supply chain is investigated, and the role of the state and that of the free market in obtaining food are clarified. A comparative historical solution is proposed to reconstruct the food baskets of various income groups in Roman society, together with the costs of such baskets. Eventually, the value of the food annually consumed in Rome is calculated. Many historians interested in the ancient economy believe that most of Rome’s population struggled for survival on a monotonous and nutritionally inadequate diet. This thesis shows that such view is inconsistent with the available sources. The eating patterns of the inhabitants of ancient Rome were rather diversified, and food choices were mainly linked to income. In addition, broadly accepted figures regarding the size of the Roman economy are underestimated. Show less
Ten years ago, the Single Supervisory Mechanism (SSM) was created, centralizing European banking supervision. In the SSM, the European Central Bank (ECB) cooperates closely with the National... Show moreTen years ago, the Single Supervisory Mechanism (SSM) was created, centralizing European banking supervision. In the SSM, the European Central Bank (ECB) cooperates closely with the National Competent Authorities (NCAs). The unprecedented degree of integration between NCAs and the ECB leads to supervision often being a joint exercise. SSM composite procedures are a specific type of such a joint exercise.Composite procedures culminate in a final ECB or NCA decision, yet are based on input from both. This integrated decision-making forms a paradox with the European system of judicial protection, which to an important extent remains to be organised dualistically. In short, national courts still review only national acts while the EU Courts, in principle, review only EU acts.This paradox raises concerns regarding effective judicial protection. This dissertation aims to investigate whether the EU principle of effective judicial protection is currently safeguarded within the SSM, particularly where it concerns composite procedures. It examines both the action for annulment and the action for damages, addressing the interplay between the EU and Dutch national legal framework. It is concluded that effective judicial protection is not always achieved. The dissertation therefore proposes several recommendations aimed at enhancing effective judicial protection within SSM composite procedures. Show less
This dissertation has approached marriage and divorce among Muslims in ‘peripheral’ areas in Indonesia from various angles, employing legal analysis as well as historical and ethnographic research.... Show moreThis dissertation has approached marriage and divorce among Muslims in ‘peripheral’ areas in Indonesia from various angles, employing legal analysis as well as historical and ethnographic research. The study seeks to understand the intricate relationship between the interpretation of Muslim family law as promulgated by the state, and the different forms of empirical laws or norms operating within Indonesia’s multicultural Muslim society. Focussing on Mukomuko in Bengkulu province, on the west coast of Sumatra, this study discusses marriage and divorce practices in three different but connected sites or contexts: i.e. everyday practices at societal level; relevant cases available in the first instance Islamic courts; and landmark decisions and developments within the Islamic Chamber of the Indonesian Supreme Court, at the national level. Mukomuko is a case in point, in which the state’s patriarchally-inclined Islamic law conflicts with matrilineal Muslim community traditions. On the basis of ten months of fieldwork I conducted in this region and during several subsequent shorter visits from 2017 to 2019, this study reveals that even though marriage and divorce practices in Mukomuko are increasingly influenced by the state’s patriarchally inclined Islamic law, matrilineally-inclined Islamic law and its institutional actors have shown remarkable resilience. Show less
This PhD thesis addresses southern African archaeology, emphasizing the importance of considering geoarchaeological context when using archaeological remains to support hypotheses. It focuses on... Show moreThis PhD thesis addresses southern African archaeology, emphasizing the importance of considering geoarchaeological context when using archaeological remains to support hypotheses. It focuses on Umhlatuzana and Umbeli Belli rockshelters, conducting a comprehensive stratigraphic analysis for a deep understanding of their depositional history and archaeological context.Umhlatuzana's stratigraphic sequence reveals primary, unaltered depositional micro-layering throughout, challenging assumptions of sediment movement. Bioturbation features are present but do not significantly impact lithic assemblages.Umbeli Belli rockshelter shows intense percolating water activity, causing poor preservation of organic remains. Different geogenic processes and pulsed occupations form varying artifact densities and sterile zones, but overall, the archaeological context remains secure with minimal bioturbation.This research highlights the need for taphonomic studies to understand the visibility, invisibility, or absence of specific proxies in the archaeological record. In-depth geoarchaeological analysis contributes to assessing archaeological record completeness and revealing remnants affected by post-depositional processes.In conclusion, this study underscores the importance of geoarchaeological research in elucidating site formation processes and archaeological visibility, especially in challenging preservation conditions, like Umhlatuzana and Umbeli Belli rockshelters, providing valuable insights into southern African archaeology. Show less
Prenatal detection of congenital heart defects has been known to decrease mortality and morbidity in children born with such defects. This thesis describes the increase of prenatal detection of two... Show morePrenatal detection of congenital heart defects has been known to decrease mortality and morbidity in children born with such defects. This thesis describes the increase of prenatal detection of two outflow-tract anomalies, by adding an additional mandatory plane to the national screening program. The second part of this thesis, studies the development of the fetal brain in children affected by congenital heart defects. These children are known to have worse neurodevelopmental outcome than their healthy counterparts. There is some evidence describing a prenatal origin of the delay in neurodevelopment. In the studies that were described in part two of this thesis, we have used a deep-learning algorithm that can assess the maturation (or development) of the fetal brain. We have found small delays in brain maturation as compared to healthy control fetuses. The clinical significance of these outcomes however, remains unclear. A multifactorial cause of brain damage in children with CHD is much more likely. Whatever the exact cause of the long-term neurodevelopmental delay in children with congenital heart defects is, the correlation is undeniable. And thus, expecting parents must be informed of this matter. Show less
The aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of... Show moreThe aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of vulvar and HPV-driven diseases.Firstly, this thesis focuses on the recognition and validation of imaging-based biomarkers for recognition of diseases of the skin and external genitalia. Clinical studies were performed using 3D photography, dermatoscopy optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) on vulvar HSIL, lichen sclerosus, cutaneous warts and anogenital warts. These techniques were subsequently implemented in a clinical trial in which a novel small molecule was tested for safety and exploratory efficacy for the treatment of cutaneous warts.Furthermore, this thesis explores sequencing-based biomarkers for vulvar disease, facilitating insight into the aetiology of vulvar diseases and identifying potential new therapeutic targets. The currently available literature on the vulvar microbiome composition was investigated and expanded in an observational study characterising the vulvar microbiome composition of healthy volunteers, vulvar HSIL patients and lichen sclerosus patients. Lastly, a perspective on recent developments in the field of premalignant vulvar disease is provided, with recommendations for future applications of the biomarkers studied in this thesis. Show less
There is a need for alternative methods to replace, reduce and refine (3R) animal experimentation. Combining experimental data from high-throughput in vitro studies with in silico modeling is a... Show moreThere is a need for alternative methods to replace, reduce and refine (3R) animal experimentation. Combining experimental data from high-throughput in vitro studies with in silico modeling is a promising approach to unravel the effect of chemicals on living cells and to gain a better understanding of the processes leading to adverse effects. Exposure to chemicals can activate various stress response pathways that limit the amount of cellular damage, help cells to recover or orchestrate irreversible cell fates such as apoptosis. In this thesis, we use experimental data and current knowledge on stress pathway activation and cell fate to create different types of computational models. With these models, we mathematically describe intracellular protein signaling cascades activated upon exposure to various compounds and their link to cell fate. In this way, we integrate molecular-level biological processes to cell-level phenomena such as cell cycle progression, senescence and necrosis, and generate new hypotheses about the mechanisms underlying adversity. Show less
The radio sky harbours both galactic and extragalactic sources of arcminute- to degree-scale emission of various physical origins. To discover extragalactic diffuse emission in the Cosmic Web... Show moreThe radio sky harbours both galactic and extragalactic sources of arcminute- to degree-scale emission of various physical origins. To discover extragalactic diffuse emission in the Cosmic Web beyond galaxy clusters, one must image low–surface brightness structures amidst a sea of brighter compact fore- and background sources. Angularly separating the faint from the bright radio sky requires high-quality ionospheric calibration. This thesis introduces new advances in and investigations into ionospheric calibration, the degree-scale Milky Way foreground, and two sources of megaparsec-scale emission in cosmic filaments: giant galactic outflows and cosmological structure formation shocks. Giant galactic outflows (or ‘giant radio galaxies’) are generated by the jets of active supermassive black holes, and transport relativistic leptons, entrained atomic nuclei, heat, and magnetic fields from the centres of galaxies to their outskirts and beyond. These outflows embody the most energetic pathway by which galaxies respond to the Cosmic Web around them. Structure formation shocks around filaments are a generic, but still elusive, prediction of cosmological simulations and trace the gravitational flow of matter from proto-voids to filaments. Both phenomena inform on the strength, topology, and origin of magnetic fields in the Cosmic Web. Show less
To generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims... Show moreTo generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims to contribute to the knowledge on SUMO regulated oncogenesis, understanding the consequences of abolishment of SUMO signaling and exploiting the potential of SUMO E1 inhibitors. To this end, we describe SUMO as a potential biomarker for cancer aggressiveness and increase our understanding on SUMO’s role in cell cycle progression. We exploited the potential of SUMO E1 inhibition by combining with hypomethylating compound 5-Aza-2’ deoxycytidine, leading to increased cytostatic efficacy. Furthermore, we repurposed the SUMO E1 inhibitor TAK981 and hypomethylating drug 5-Aza-2’ deoxycytidine to improve engineered TCR (eTCR) T cell therapy and broaden our understanding of its immunomodulatory potential. Show less
This thesis discusses several questions regarding the double ramification cycle as a Chow class on the moduli space of stable n-pointed genus g curves using tools from so-called logarithmic... Show moreThis thesis discusses several questions regarding the double ramification cycle as a Chow class on the moduli space of stable n-pointed genus g curves using tools from so-called logarithmic geometry. It contains two extracts from articles; the first of these defines the universal double ramification cycle on the Picard stack of n-pointed genus g curves with a line bundle of fixed degree, which is a way to also include the generalisations that are called twisted double ramification cycles. The second article introduces the logarithmic double ramification cycle in the logarithmic Chow ring. The logarithmic double ramification cycle is proven to be ‘logarithmically tautological’ and it helps us prove that the double-double ramification cycle (or the good definition for ‘intersecting double ramification cycles’) is tautological – that is, these classes lie in a subring generated by ‘computable and known’ classes. The second chapter of the thesis explains and illustrates piecewise-polynomial functions, which are key to describing the forementioned ‘logarithmically tautological’, and how these functions relate to classical divisors which we use to describe tautological rings. Show less
Atherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction-associated steatotic liver disease (MASLD; previously known as non-alcoholic fatty liver disease) are a result of lipid... Show moreAtherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction-associated steatotic liver disease (MASLD; previously known as non-alcoholic fatty liver disease) are a result of lipid accumulation in the vascular wall and liver, respectively. In the body, lipids are transported between organs within lipoproteins, and thus disordered lipoprotein metabolism is closely associated with ASCVD and MASLD development. Active brown adipose tissue (BAT) combusts lipids to produce heat, and BAT activation is therefore considered a potential strategy to improve lipoprotein metabolism. In this thesis, I describe a new method of monitoring lipoprotein metabolism and BAT activity by PET-CT scan. To this end, a newly developed 18F-labeled lipid tracer was incorporated in optimized lipoprotein-like particles, and appeared to outperform 18F-deoxyglucose in tracing activated BAT. The results presented in this thesis also further confirm the usefulness of the APOE*3-Leiden.CETP mouse model for studying therapeutic interventions to improve lipoprotein metabolism. Using this translational model, I demonstrated that exercise at the end of the active phase and combined glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide receptor agonism, a strategy for treating diabetes and obesity in the clinic, are promising ways to combat both ASCVD and MASLD. Show less
Within the field of astronomy, understanding how galaxies grow and evolve from the Big Bang to the present day is a challenging and complex question. Radio observations - unhindered by dust... Show moreWithin the field of astronomy, understanding how galaxies grow and evolve from the Big Bang to the present day is a challenging and complex question. Radio observations - unhindered by dust attenuation - are a powerful tool in studying the formation of stars and subsequent buildup of galaxies. In this thesis, the distant star formation is studied using radio observations from the VLA COSMOS-XS survey specifically. In Chapter 2, we discuss the details of the sensitive COSMOS-XS survey and present the derived Euclidean-normalized source counts. In Chapter 3, we derive the dust-unbiased star formation rate density out to high redshift and present evidence for a significant underestimation of the star formation rate density based on ultraviolet observations. In Chapter 4, the focus shifts to the ‘optically dark’ population: extremely dust-obscured sources that are invisible even in deep ultraviolet imaging. We identify these sources with the COSMOS-XS survey and use them to quantify their contribution to the total star formation rate density. In Chapter 5, we present new ALMA observations of ‘optically dark’ sources and confirm the cosmic importance of ‘optically dark’ sources at high redshift. Show less
Aspects which advocate the synergy between dance medicine and dance pedagogy with the aim to prevent musculoskeletal injuries in classical ballet and contemporary dancers were investigated.... Show moreAspects which advocate the synergy between dance medicine and dance pedagogy with the aim to prevent musculoskeletal injuries in classical ballet and contemporary dancers were investigated. Specifically, aspects which have not yet been studied before, such as neuromuscular warm-up in dance, motivational climate, or injuries as stressors and their association with physical (repetitive) injury, respectively, in order to provide the basis for future research. Also, the effects of erroneous dance technique were evaluated, while a dual-approach looked into the causes which dancers perceived for their acute and overuse injuries as well as how they rated their ballet masters’ or ballet teachers’ proactive efforts to implement dance medicine into dance practice with the goal of identifying and preventing musculoskeletal injuries in their dancers. An extensive and international survey study provided retrospective data and longitudinal prospective data was collected over 6 years in a university training professional contemporary dancers. Show less
The aim of this research was to develop an effective, generative, and practical approach to enhance students’ structure-property reasoning (SPR). The approach consists of an evaluation instrument... Show moreThe aim of this research was to develop an effective, generative, and practical approach to enhance students’ structure-property reasoning (SPR). The approach consists of an evaluation instrument that assesses the level of structure-property reasoning and a teaching practice to make structure-property reasoning more explicit for students.As base of the approach, the perspective for SPR was used as model for structure-property reasoning. With this model, we aimed to represent the relationship between chemical concepts and the skill of structure-property reasoning.The SPR-instrument combines a sorting task with a mapping task based on the perspective for SPR. The instrument was tested on secondary school students and first-year chemistry students. The results showed that the SPR-instrument can discriminate between these two groups.This teaching practice consists of demonstration experiments with two design principles, namely the Predict-Observe-Explain (POE) approach and the perspective for SPR. The teaching practice was tested on Y-4 pre-university students. The results showed that the teaching practice contributed to the development of structure-property reasoning. The practicality of (re)designed demonstrations appeared to be as high as that of "traditional" demonstrations.The research showed that perspective for SPR (combined or not with POE-demonstrations) could bridge the gap in students’ chemical reasoning. Show less
